Mini-Reviews in Medicinal Chemistry, Volume 4, No. 3, 2004
Contents
New
Insights in Protein Kinase Inhibitors: Chemogenomics, Phosphoproteomics,
Structural Based Approaches and the Emergence of Resistance
Executive
Editor: Doriano Fabbro
Kinase Chemogenomics:
Targeting the Human Kinome for Target Validation and
Drug Discovery Pp.235-253
E.
ter Haar, W.P. Walters, S. Pazhanisamy, P. Taslimi, A.C.
Pierce, G. W. Bemis, F.G. Salituro and S.L. Harbeson
Targeting FLT3 Kinase
in Acute Myelogenous Leukemia: Progress, Perils, and
Prospects Pp.255-271
Michael
C. Heinrich
Therapeutically Targeted Anticancer Agents:
Inhibitors of Receptor Tyrosine Kinases Pp.273-283
Carlos
Garcia-Echeverria and Doriano Fabbro
Imatinib (STI571) Resistance in Chronic Myelogenous Leukemia: Molecular Basis of the Underlying
Mechanisms and Potential Strategies for Treatment Pp.285-299
Sandra
W. Cowan-Jacob, Valerie Guez, Gabriele Fendrich, James D. Griffin, Doriano
Fabbro, Pascal Furet, Janis
Liebetanz, Jurgen Mestan and Paul W. Manley
New Lead Generation Strategies for Protein Kinase Inhibitors – Fragment Based Screening Approaches Pp.301-311
Adrian
Gill
Exploring the Phosphoproteome
with Mass Spectrometry
Pp.313-324
Eric
C. Peters, Ansgar Brock and Scott B. Ficarro
The Emergence of Selective 5-HT2B
Antagonists Structures, Activities and Potential Therapeutic Applications Pp.325-330
G.
Poissonnet, J.G. Parmentier,
J.A. Boutin and S. Goldstein
Small Molecule Antagonists of the Tachykinin NK2 Receptor Pp.331-340
Daniela
Fattori, Maria Altamura and Carlo Alberto Maggi
Abstracts
[Back to top] Kinase Chemogenomics:
Targeting the Human Kinome for Target Validation and
Drug Discovery
E.
ter Haar, W.P. Walters, S. Pazhanisamy, P. Taslimi, A.C.
Pierce, G. W. Bemis, F.G. Salituro and S.L. Harbeson
Chemogenomics is a gene family-based approach to drug
discovery and target validation. This review will summarize the application of
this interdisciplinary approach to the protein kinases
of the human genome with emphasis upon the synergies and efficiencies to be gained.
Specific examples from the SAPK-family will be discussed.
[Back to top] Targeting FLT3 Kinase
in Acute Myelogenous Leukemia: Progress, Perils, and
Prospects
Michael
C. Heinrich
Activating
mutations of the FLT3 receptor tyrosine kinase are
the most common recurring genetic abnormality in acute myelogenous
leukemia (AM). Inhibition of FLT3 kinase activity by
small molecule inhibitors has been proposed as a novel therapeutic approach
AML. The pre-clinical and clinical development of candidate FLT3 inhibitors
will be reviewed.
[Back to top] Therapeutically Targeted Anticancer Agents:
Inhibitors of Receptor Tyrosine Kinases
Carlos
Garcia-Echeverria and Doriano Fabbro
The rationale to target
receptor protein tyrosine kinases (RPTKs) as an approach to cancer chemotherapy has continued
to become more compelling with time. Preclinical and clinical data strongly
support the involvement of specific RPTKs in the
formation and progression of a subset of solid and liquid tumors. The advances
in our understanding of the oncogenic activation of
these receptors have been matched by the identification of new structural
classes of kinase inhibitors that exhibit enormous
improvements with regard to potency, specificity and efficacy. This article
summarizes current knowledge of the most promising RPTK inhibitors in clinical
trials or known to be in late stage preclinical development.
[Back to top] Imatinib (STI571)
Resistance in Chronic Myelogenous Leukemia: Molecular
Basis of the Underlying Mechanisms and Potential Strategies for Treatment
Sandra W. Cowan-Jacob, Valerie Guez, Gabriele Fendrich, James D. Griffin, Doriano Fabbro, Pascal Furet, Janis Liebetanz, Jurgen Mestan and Paul W. Manley
Following the
paradigm set by STI571, protein tyrosine kinase
inhibitors are emerging as a promising class of drugs, capable of modulating
intracellular signaling and demonstrating therapeutic potential for the
treatment of proliferative diseases. Although the
majority of chronic phase CML patients treated with STI571 respond, some
patients, especially those with more advanced disease, relapse. This article
reviews the reasons for relapse and, in particular, analyses resistance resulting
from Bcr-Abl tyrosine kinase
domain mutations at the molecular level. Arguments are based upon the structure
of the STI571-Abl complex, which is compared to the crystal structures of
PD173955-Abl and PD180970-Abl, which bind to the kinase
differently. Strategies to potentially circumvent or overcome resistance are
discussed.
[Back to top] New Lead Generation Strategies for Protein Kinase Inhibitors – Fragment Based Screening Approaches
Adrian
Gill
The protein kinase superfamily represents
both an enormous opportunity and a unique challenge for drug discovery. Protein
kinases play central roles in the cellular economy
and it is well known that a large number of diseases involve aberrant protein kinase activity. This review discusses how fragment based
screening strategies, such as virtual screening, NMR and high-throughput X-ray
crystallography are being employed to identify new chemo-types to produce the
next generation of protein kinase inhibitors.
[Back to top] Exploring the Phosphoproteome
with Mass Spectrometry
Eric
C. Peters, Ansgar Brock and Scott B. Ficarro
Protein phosphorylation is a reversible post-translational
modification crucial in the control of numerous regulatory pathways.
Understanding the highly interconnected nature of such networks requires new
broader-scale analysis techniques. This report summarizes recent advances in
the use of mass spectrometry to assess phosphorylation
events in ever more complex systems.
[Back to top] The Emergence of Selective 5-HT2B
Antagonists Structures, Activities and Potential Therapeutic Applications
G.
Poissonnet, J.G. Parmentier,
J.A. Boutin and S. Goldstein
5-HT2 receptors
mediate a large array of physiological and behavioral functions in humans via
three distinct subtypes: 5-HT2A, 5-HT2B and 5-HT2C. While selective 5-HT2A
antagonists have been known for some time, knowledge of the precise role played
by the 5-HT2B receptor was hampered by the existence of solely 5-HT2B/5-HT2C
mixed antagonists.
However, selective
5-HT2B antagonists began recently to emerge in the literature. Indeed, four
structural classes belonging to the piperazine, indole, naphthylpyrimidine and tetrahydro--carboline scaffolds were reported. In
this paper, we will briefly review the structural and pharmacological features
of selective 5-HT2B antagonists, including patent literature of the last five
years.
[Back to top] Small Molecule Antagonists of the Tachykinin NK2 Receptor
Daniela
Fattori, Maria Altamura and Carlo Alberto Maggi
The NK2 receptor
(member of the tachykinin receptor family) is mainly
located in the smooth muscle of the urinary, respiratory and gastrointestinal
tracts, with limited presence in the CNS. This has raised interest in tachykinin NK2 receptor antagonists for the treatment of
urological disorders, asthma. This review outlines progress done after 1998 in
the field of NK2 small molecule antagonists, both acting on the NK1/NK2,
NK2/NK3, NK1/NK2/NK3 receptors and selective for the
NK2 one.